MRCT Center Expanded Access to and Institutional Review · 12/1/2017 · survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from

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ExpandedAccesstoInvestigationalProductsAPracticalApproachforSponsors,Physicians,andInstitutionalReviewBoards

TableofContents1. ResourcesforSponsors:EvaluationofRequestsforInvestigationalProductsThroughthe

IndividualPatientExpandedAccessProgram............................................................................21.1Background...............................................................................................................................21.2OverarchingPrinciplesforSponsorConsiderationsofExpandedAccess...............................31.3ConsiderationsforSponsorsinDecision-MakingaboutExpandedAccess.............................41.4TransparentCommunicationofSponsorPoliciesandProcesses...........................................8

2. ResourcesforTreatingPhysicians:IndividualPatientExpandedAccesstoInvestigational

NewDrugs..................................................................................................................................92.1Introduction..............................................................................................................................92.2ConsiderationsforPhysiciansinDecision-MakingRegardingExpandedAccess....................92.3RegulatoryBackground..........................................................................................................122.4Physician’sToolkit..................................................................................................................16

3. ResourcesforIRBs/RECs:EvaluationofRequestsforInvestigationalProductsThroughthe

IndividualPatientExpandedAccessProgram..........................................................................283.1Background.............................................................................................................................283.2ConsiderationsforIRBsinDecision-MakingaboutExpandedAccess...................................293.3GlossaryandDefinitions.........................................................................................................30

4. ResourcesandReferences.......................................................................................................31

TableofFigures

Figure1:TypesofExpandedAccessThatOccurDuringtheFDA’sDrugDevelopment/ApprovalProcess...............................................................................................................13Box1:Non-EmergencyUseandEmergencyUse........................................................................16Box2:NecessaryPatientandProductInformation....................................................................17Box3:ChecklistforEmergencyandNon-EmergencyExpandedAccessProcedures................21


1. ResourcesforSponsors:EvaluationofRequestsforInvestigationalProductsThroughtheIndividualPatientExpandedAccessProgram

1.1Background

Theroleofthepharmaceuticalanddevicecompaniesisgenerallytodiscover,developandmarketsafeandeffectivedrugs,biologicsanddevices.Theprocessofdrugdevelopment—fromtargetidentification,leaddrugoptimization,preclinicaldevelopmentandclinicalexperimentation,toreviewandapprovalbycognizantregulatoryauthorities—isalongandcomplexprocess.Thedeterminationofsafetyandefficacyofaninvestigationalproductistypicallyaccomplishedthroughwell-designed,prospective,controlledclinicaltrials.Notallpatients,however,haveaccesstothoseclinicaltrials,foreitherclinical,logistical,practical,orotherreasons.Forseriouslyillpatientswhoareunabletoparticipateinaclinicalstudyandforwhomnoequivalentorsatisfactorytreatmentoptionisavailable,accesstoaninvestigationalproductoutsideofaclinicaltrialmaysometimesbeconsidered.Expandedaccess(alternativelytermed“compassionateuse,”“preapprovalaccess,”or“earlyaccess”)programshavebeendevelopedtoprovideaccesstoinvestigationalorunlicensedproducts(drugs,biologics,anddevices)tosuchpatients.Asdescribedmorefullybelow,sponsorpoliciesregardingexpandedaccessprogramsshouldbeaccessibleandclear.

Applicablenationallawsandregulationsgovernthisprocesswithineachcountry.Forexample,theEuropeanMedicinesAgencyhasdescribedhowprogramsmaybecreatedintheEuropeanUnion(EMA,2010),aswellitsownroleintheseprograms(intheEMAtermed“compassionateuse”)(EC,2004,RegulationNo.726/2004).Notably,however,eachEUMemberStateisresponsibleforregulating,coordinatingandimplementingitsownexpandedaccess(compassionateuse)programs,includingforindividualpatientsonanamedbasis(EC,2001,Directive2001/83).Thesedescribecompassionateuseprogramsforgroupsofindividualpatients,andaccessisarrangedthroughtheirdoctor,theproductmanufacturerandtheregulatoryauthority.IntheUK,theMedicinesandHealthcareproductsRegulatoryAgency(MHRA)isresponsibleforoverseeingthe“earlyaccesstomedicinescheme(EAMS),”athreestepprocess(MHRA,2014).InIndia,pertheDrugsandCosmeticAct1940andRules1945,theDrugControllerGeneralofIndia(DCGI)providesoversightofuseofanunapproveddruginthecountrybyapatient(Rule36)orbyahospitalorinstitution(Rule34)(CDSCO,2014).CodifiedguidanceforexpandedaccessincertaincountriessuchasChinadoesnotappeartobereadilyavailable.Itis,obviously,veryimportanttoconsultthecognizantnationalregulatoryagencypriortoproceedingwithexpandedaccessinordertounderstandspecificrequirementsandregulations.

IntheUS,onSeptember16,2016,theUSDepartmentofHealthandHumanServices(HHS)issuedtheFinalRuleforClinicalTrialsRegistrationandResultsInformationSubmission,referredtoas“FinalRule”asrequiredbyTitleVIIIoftheFoodandDrugAdministration(FDA)


AmendmentsActof2007(FDAAA).Pertainingtoexpandedaccess,theFinalRulerequirestheSponsortodiscloseinformationaboutwhetherexpandedaccesstoaninvestigationalproductisavailableontheStudyRegistrationandResultspostingontheUSportalofwww.clinicaltrials.gov.CompliancewithregardtoExpandedAccesswillrequireSponsorstocompleteaseparate“expandedaccessregistration”recordforanyunapproveddrugproductthatisavailablethrougheitheraprotocolorindividualINDexpandedaccessprogram.April18,2017istheeffectivedateforcompliance.

SubsequenttothecodificationoftheFinalRule,the21stCenturyCuresActwassignedintolawinDecember2016.Section561AoftheActrequiresdrugmanufacturerstopubliclydisclosetheirexpandedaccesspolicyandproceduresformakingarequest.

IntheUS,theFoodandDrugAdministration(FDA)hasdefinedthreevariationsoftheexpandedaccessprogram:oneeachforlargepopulations(“treatmentIND”),for“intermediatesize”populations,andfortheindividualpatient(21C.F.R.§312SubpartI).Herewediscussonlyprograms,includingthoseforemergencyuse,designedtoaddressphysicianrequestsonbehalfoftheirindividualpatients(21C.F.R.§312.310).WeaddressspecificallythoseprogramsregulatedintheUS,althoughtherelevantissuesandoverarchingconsiderationsareapplicabletoanydecisionregardingexpandedaccesstoinvestigationalproductsandarecommonamongallcountriesandtheirnationalregulatoryagencies.Theseconsiderationsarediscussedfurtherbelow.

1.2OverarchingPrinciplesforSponsorConsiderationsofExpandedAccess

Asathresholdconsideration,theapplicationofcertainethicalprinciplesshouldguidedecisionmakingwheneveranexpandedaccessrequestisconsidered:

• Allpatientsshouldbetreatedfairlyandequivalently.

• Patientsshouldnotbeputatriskofunnecessaryharm.

o Theriskofpotentialharmisnotgreaterthantheriskofthediseaseorcondition.

o Someinformationastothepotentialclinicalbenefit,potentialharm,doseandproposedtreatmentplanisavailable.

• Adequatesupplyoftheinvestigationalproductisorcanbemadeavailable.

o Theinvestigationalproductmustbeinsufficientsupplynotonlyforthetreatmentprogramofthepatientandforsimilarfuturepatients,butforthedrugdevelopmentprogram.

o Timelycompletionofappropriately-designedclinicaltrialsisthefastestmethodtodevelopdataforsubmissiontotheregulatoryagencyfortheirreviewandapproval,therebyguaranteeingavailabilityofproductsthataresafeandeffectivetothebroadestgroupofindividuals.


1.3ConsiderationsforSponsorsinDecision-MakingaboutExpandedAccess

Thesponsormustdecidewhethertoprovidetheinvestigationalproductforthepotentialbenefitofanindividualpatientinresponsetoarequestfromaphysician.Thisdecisionisnotalwaysstraightforward.Asmuchasthesponsormaywishtoassist,therearecountervailingconsiderations.Istheresufficientevidencethatthepotentialbenefitoftheinvestigationalproductbalancespotentialrisksandharms?Willprovisionoftheinvestigationalproductimpedetheprogressofclinicaltrialsforanyreason(e.g.,bylimitingdrugsupplyorbypermittingpatientswhocouldbeclinicaltrialparticipantsaccesstoproductoutsidethetrial,therebydelayingtrialrecruitmentorevenbiasingtheresults)?Willtheinvestigator(here,thetreatingphysician)executehisorherresponsibilitiessoasnottojeopardizethedrugdevelopmentprogram?Sponsorsmayhavesignificantdataabouttheinvestigationalproductsthatarenotavailabletothepublic:whatmayseemstraightforwardtothetreatingphysicianandtothepatientmaybefarmorecomplexwhenallthedataareknown.Herewereviewconsiderationsofandbythesponsorwhenapproachedbyanindividualphysicianforindividualpatientexpandedaccess.Forthediscussionbelow,weassumethatnointermediate-sizeexpandedaccessprogramortreatmentINDisopenfortheinvestigationalproduct,asthatwouldbethemostavailableandstraightforwardpathwayforaccess.Weintendtheseconsiderationstobehelpfulbothforthesponsoraswellasforthephysician,patient,andinstitutionalreviewboard(IRB)/researchethicscommittee(REC)tounderstandthefactorsthatinformthesedecisions.

1. Whatisknownaboutthepatient,thepatient’scondition,andthesuitabilityandavailabilityofaclinicaltrial?

a. Doesthepatienthaveaseriousorimmediatelylife-threateningdiseaseorcondition?Intheabsenceofaseriousorlife-threateningdiseaseorcondition,thepatienthastimetowaitfordefinitivedatatoemergeregardingsafetyandefficacy.

i. SeriousdiseaseorconditionisdefinedbytheFDAasadiseaseorconditionassociatedwithmorbiditythathassubstantialimpactonday-to-dayfunctioning.Short-livedandself-limitingmorbiditywillusuallynotbesufficient,butthemorbidityneednotbeirreversible,provideditispersistentorrecurrent.Whetheradiseaseorconditionisseriousisamatterofclinicaljudgment,basedonitsimpactonsuchfactorsassurvival,day-to-dayfunctioning,orthelikelihoodthatthedisease,ifleftuntreated,willprogressfromalesssevereconditiontoamoreseriousone(FDA,2009,21C.F.R.§312.300).

ii. Immediatelylife-threateningdiseaseorconditionisdefinedbytheFDAasastageofdiseaseinwhichthereisreasonablelikelihoodthatdeathwilloccurwithinamatterofmonthsorinwhichprematuredeathislikelywithoutearlytreatment(EMA,2010).


b. Hasthepatientexhaustedallothersatisfactoryorcomparableapprovedtreatmentsforthediseaseorcondition?Therisks,safetyprofileandpotentialbenefitsoftheinvestigationalproductareunknownorincompletelyknown;allotheravailableapprovedtreatmentsshouldbegivenorconsideredinadvanceoftheexpandedaccessrequest.

c. Arethereanysuitableandavailableclinicaltrialsinwhichthepatientcouldparticipate?

i. Isthediseaseorconditionforwhichaccesstotheproductisbeingrequestedalreadybeingaddressedbyanopenclinicaltrial(i.e.atrialactivelyenrolling)throughwhichthetestproduct(orsimilarproduct)couldbemadeavailable?

ii. Isthepatienteligibleforanongoingclinicaltrial?Ifnot,whatisthenatureoftheineligibility?Istheineligibilityrelatedtothesafetyorefficacyoftheinvestigationalproduct?Forinstance,aclinicaltrialforaninvestigationalagentthatisexcretedviathekidneyorlivermayexclude,forsafetyreasons,individualswithpoorrenalorhepaticfunction.

iii. Ifthepatientiseligibleforaclinicaltrial,isthereanappropriatesitetowhichthepatientmaybereferred?Isreferralpracticalandpossible?Forinstance,significanttravelforaseriouslyillindividualmaynotbepossible,evenifallotherissuescouldberesolved.Isitpossibleandpracticaltoopenasiteforenrollmentthatcouldaccommodatethepatientandsimilarlysituatedpatientswhomayalsoseekaccesstothetestproduct?

2. Whatisknownabouttheinvestigationalproductanditsavailability?Itisimportanttorememberthatinvestigationalproductshavenotyetbeenreviewedorapprovedbythecognizantnationalregulatoryagency.Thepotentialrisksandbenefitsarenotyetestablishedandnotfullyknown.Nevertheless,thesponsormayhaveaccesstoinformationabouttheproductthattherequestingphysiciandoesnot.

a. Doesthesponsorhavesafetyorriskinformationabouttheinvestigationalproduct,whetherpublishedornot,thatisapplicabletothespecificpatientandwouldinformthedecision?

i. Ifitisdecidedthattheinvestigationalproductwouldnotbeappropriateforthediseaseorconditionorforthepatient,isitpossibletosharetheexplanationwiththerequestingphysician?

b. Ifitwouldbemedicallyjustifiedtoprovidetheinvestigationalproducttothepatient,isthetreatmentcourseknown,andistheamountofproductrequiredknown?Istheresufficientsupplyoftheproductsothattheprogressofongoingandplannedclinicaltrialswillnotbeadverselyaffected?Ifnot,canproductionbeincreasedorscaledtoaccommodate?


i. Timelycompletionofwell-designedandexecutedclinicaltrialsisthemostrapidmethodtoassesssafetyandefficacyofaninvestigationalproduct;datacanthenbereviewedbytheFDA(orappropriatenationalregulatoryagency).Approvalwillpermitgeneralaccessbyanddisseminationtoallpatients.Anycauseofappreciabledelayofthedrugdevelopmentprogramisproblematic.

c. Ifsufficientdrugsupplyisavailable,andthepatientisanappropriatecandidatefortheinvestigationalproduct,ismarketingapprovallikelytobepursuedintheUnitedStates(orappropriatecountry)?Ifnot,thesponsorshoulddeterminewhethertheprovisionofdrugwouldbefairandequitable,asexpandedaccessmayneedtobecontinuedinthatnationaljurisdiction,forthatpatient,eventhoughotherpatientswouldnothavesuchaccess.Thispresentslogisticalandethicalissues.Inanyevent,theFDA(ortheappropriateregulatoryauthoritiesofthecountryinwhichtheinvestigationalproductwouldbesupplied)mustbeconsultedandmustconcurwithanydecisiontoofferaccess.

3. Ifitisdecidedthattheinvestigationalproductcanandwillbeprovided,doesthetreatingphysicianunderstandhisorherresponsibilitiesintheprocess?

a. Isthetreatingphysicianfamiliarwiththecountry,region,and/orstatespecificlegalandregulatoryrequirementsforadministeringtheinvestigationalproduct?Willthetreatingphysicianapplyforaninvestigationalnewdrug(IND)applicationtotheFDA?

b. Isthetreatingphysicianawareofhisorherresponsibilitiesintheprocess,including:

i. ApplyingtoandobtainingapprovalfromtheFDA,ifrequired,andaresearchethicscommittee(REC)oraninstitutionalreviewboard(IRB)priortoanyprovisionoftheinvestigationalproduct?

ii. Obtaininganddocumentingappropriateinformedconsentfromthepatientorhisorherlegallyauthorizedrepresentativepriortotreatment?

iii. Maintainingaccuraterecordsofthecasehistoryandobservationsrelatedtoprovisionofproduct,includingadverseevents?

iv. Maintainingaccuratedocumentationoftheadministrationofinvestigationalproduct,includingdates,quantityanduse?

v. Reportingobligationstotheregulatoryauthority?TotheIRB/REC?Tothesponsor?

vi. Communicatingwiththepatientthroughouttheprocess?

vii. Maintainingconfidentialityofinformationaboutthepatientandabouttheinvestigationalproduct?


viii. ComplyingwithapplicableFDA(national)lawsandregulations.

c. IfthetreatingphysicianwillapplytotheFDAforpermissiontoadministertheinvestigationalproduct,willthesponsorprovidealetterofauthorization(LOA)orotherdocumentation(e.g.,theinvestigator’sbrochureandtheINDapplication)?WillthesponsorallowthetreatingphysiciantorelyontheinformationintheexistingIND?Ifnot,whynotandisitpossibletosharetheexplanationwiththerequestingphysician?

4. Arethereotherconsiderations(e.g.,financialorotherresourcerequirements)beforeafinaldecisionismade?

Whenthefinaldecisionismade,thesponsorshouldcommunicatewiththetreatingphysician.Ifprovisionoftheinvestigationalproductisnotpossible,itishelpfultoexplainthedecision-makingprocesstothephysician,aswellasanypossiblealternativesforthepatient.Forinstance,thephysicianshouldbeinformedastowhichchangesinclinicalconditionmightpromptre-reviewbythesponsoroftheexpandedaccessrequestforthepatient.

Ifthedecisionismadetoprovideexpandedaccesstotheinvestigationalproduct,thesponsorshould(1)provideaLOAtothephysician,(2)followingFDAandIRB/RECapproval,arrangefordistributionandtransportoftheproductand(b)communicatespecificinstructionstothetreatingphysician(e.g.,timingofreportingofseriousadverseeventsorunanticipatedproblems,documentationrequirements),providingappropriateformsandtemplatesifavailable.IfthesponsorhasdecidedtoallowthephysiciantorelyupontheinformationintheexistingIND,thesponsorshould(4)provideacopyoftheinvestigator’sbrochureandtheINDapplicationtothephysician.Itshouldbeclearthattheapprovalisforthespecificpatientandthatremainingproductmustbereturnedtothesponsorordestroyed(anddocumentationprovided)andnotadministeredtoanotherindividual,evenonewithasimilarclinicalhistory.Further,anylimitationstofutureuseshouldbeclarified(e.g.thatthesponsorcanprovideinvestigationalproductforthetreatmentcourseoutlined,butnotautomaticallyornecessarilyforanychangestothattreatmentplan).

Thesponsorshouldbeawarethatprovisionofexpandedaccessinonesetofcircumstancesimpliesthatthesponsorwillconsidersimilarrequestsinthefuture.Fairnessandequityexpectationsshouldbeconsideredinadvance.

Finally,thesponsorshouldconsiderwhetherthenationalregulatoryauthoritypermits(orrequires)fulldatagatheredduringexpandedaccesstreatmenttobereportedtothesponsorandpossiblyusedforlaterregulatorysubmissions.Somejurisdictionsdonotallowsuchreportinganduseofdata,whileotherjurisdictionsmaynothaveaddressedthisissue,andsomemayrequirereportingofseriousadverseeventsandunanticipatedproblemsevenintheexpandedaccesssetting.Inanyevent,itmaybeimportantforasponsortoworkwiththetreatingphysicianandthecognizantregulatoryagencytoanticipatethisissue,andaddressitexplicitlyintheapplicationforexpandeduseandtheinformedconsent.


1.4TransparentCommunicationofSponsorPoliciesandProcessesThenewFinalRuleandthe21stCenturyCuresActrequirepharmaceuticalanddevicemanufacturerstomaketheirpoliciesforprocessing,evaluating,andrespondingtorequestsforexpandedaccesspubliclyavailable.Thepolicyistooutlinewhetherandwhenexpandedaccesstoaninvestigationalproductwillbeconsidered,andtheprocessbywhichtreatingphysicianscanrequestaccessifappropriate.TheActdoesnotrequirecompaniestoofferexpandedaccess.Companiesaremandatedtoprovide,atminimum,thefollowinginformation:

a. Contactinformationforfacilitatingorsubmittingarequest

b. Proceduresformakingarequest

c. Criteriaforevaluatingarequestandresponsestoarequest

d. Anticipatedtimelineforacknowledgingreceiptofarequest

e. Hyperlinkorreferencetoclinicaltrialrecordaboutarequestedinvestigationaldrug

Theavailabilityandaccessibilityofaclearandtransparentprocessforrequestscanassurecanassurefairnessanddeliberatenessintheprocessandhelptoforestallpolitical,media,regulatoryandethicalcontroversies.Werecommendthatpharmaceuticalanddevicecompaniesmaketheseprocessesandpoliciesreadilyaccessibleinordertoaidphysiciansandpatientswhoarenavigatingtheprocessofrequestingexpandedaccess.WealsorecommendthatpharmaceuticalanddevicecompaniesconsiderparticipatingintheReagan-UdallFoundationfortheFDAExpandedAccessNavigatorprogram(http://navigator.reaganudall.org)[email protected].


2. ResourcesforTreatingPhysicians:IndividualPatientExpandedAccesstoInvestigationalNewDrugs

2.1Introduction

Theexpandedaccessprogramhasbeendevelopedtoprovideaccesstoinvestigationalorunlicensedproducts(drugs,biologics,anddevices)toseriouslyillpatientswho(1)havenoothersatisfactoryorcomparabletreatmentoptionsand(2)areunabletoparticipateinaclinicalstudy.Generally,theexpandedaccessprogram(sometimestermed“compassionateuseprogram”or“preapprovalaccessprogram”)appliestoinvestigationalproductsthatarenotapprovedforanypurposeinthecountrywhereaccessissought.1Locallawsandregulations,aswellasmanufacturers’orpharmaceuticalcompanies’policies,governtheprocessandapproval;anyusemustconformtosuchlaws,regulations,andpolicies.Beforediscussingtheprocessbywhichaphysicianrequestsexpandedaccesstoaninvestigationalproduct(drug,biologic,ordevice)foranindividualpatient,itisimportanttoconsiderwhethersucharequestisreasonableandinthebestinterestsofthepatient.Understandinghowtoapproachexpandedaccesshasbecomeparticularlyrelevant,aspatientsaremoreactiveparticipantsintheirowncareandinformationismorereadilyavailablethroughtheInternetandsocialmedia,amongothermethods.Further,intheUS,since2014,themajorityofstates2havepassedwhataretermed“Right-to-Try”lawsthatallowpatients,undercertaincircumstancesandthroughtheirphysician,therighttoaskacompanydirectlyforaccesstoaninvestigationalproduct,bypassingFDAreviewandapproval.Todate,theselawshavenotbeentestedinsituationsFDAhasbeenbypassedtoobtainaccesstoaninvestigationaldrug.Further,Thus,aphysicianshouldunderstandtheissuesinvolvedinexpandedaccessinordertobeabletoadvisepatients,ifasked,and/ortoinitiatesuchrequests,asappropriate.

2.2ConsiderationsforPhysiciansinDecision-MakingRegardingExpandedAccess

IntheUS,expandedaccesstoinvestigationalproductsisonlyavailabletopatientsthat(1)haveaseriousorlife-threateningillness,(2)haveexhaustedallothertherapeuticoptionsandhavenocomparableorsatisfactoryalternatives,(3)arenoteligiblefororcannotparticipateinongoingclinicaltrials,and(4)understandandagreetotherisksoftheinvestigationalproduct.

Physicianshaveafiduciaryresponsibilitytotheirpatients,andinallinstances,aremotivatedto

1Generally,anapprovedproductcanbeprescribedforanindividualpatienttotreatan“off-label”diseaseorindication;thereisnoneedtoengageinanexpandedaccessprogram.Rarelyhowever,anexpandedaccessprogramisnecessary(e.g.intheUS,whenproductavailabilityislimitedbyariskevaluationandmitigationstrategy[REMS]program)orpreferable(e.g.earlyuseinaneonatalICUsettinginwhichriskishighandexperienceislacking).Thesespecialcasesfollowthesameprocessasthatdescribedhere.2AsofOctober2017,38stateshavepassedRighttoTrylaws.Notably,theRighttoTryLawsdonotrequirephysicianstoprescribeunapprovedproducts,manufacturersorcompaniestoprovideinvestigationalproducts,norinsurancecompaniestopayforthem.


determinewhatisinthebestinterestoftheirpatient.Intheabsenceoftherapeuticoptionsforacriticallyillindividual,thechoicetopursueexpandedaccessmayseemapparent;however,itisimportanttorecognizetherisks,bothknownandunknown,ofaninvestigationalproductaswellastheunknownanduncertainbenefit.Indeed,asclinicaltrialsareoftenongoing,therelevantdatatodeterminesafetyandefficacyarestillincomplete.

Drugdevelopmentisalongandcomplexprocess.Preclinicalstudiesgenerallyincludeanimalstudiesandsomeevaluationfortoxicity.PhaseIclinicaltrialsassesssafety,PhaseIItrialsexposeadditionalpatientstotheproducttorefinewhetherornotthereisevidenceofefficacyandsafety,butitisnotuntilPhaseIIItrials—socalled“registrationtrials”—thatsufficientdataarecollectedtodetermineefficacyandsafetywithstatisticalsignificance.Thesedataarethensubmittedtothecognizantregulatoryauthorityforitsreviewandapproval.Thusadministrationofaninvestigationalproduct,whetheradrug,biologic,ordevice,isnotwithoutrisk:notonlymaytheinvestigationalproductnot“work”(orbeoftherapeuticbenefit)butitmaydoharm;toxicityispossible.Thephysician—andthepatient—mustappreciatethelimitationsofcurrentknowledgeandthepotentialharmthatadministrationoftheinvestigationalproductmaycauseandknowthatthemajorityofinvestigationalproductsthatbegintobetestedinhumansfailandareneverbroughttomarket.3

Notwithstandingthiscaution,thepatientwhoexploresexpandedaccessfacesfewalternativeoptions:atherapeutictrialofanunknownorincompletelyknowninvestigationalproduct,comfortmeasures,supportivecare,orother.Inthesecases,thephysicianisresponsibleforexploringtheoptionswiththepatient,interpretingwhatisknownandunknown,andeducatingthepatientabouttherisksandunknownbenefitsofexpandedaccess.Thephysician’sroleistobehelpfultothepatientandtobesatisfiedthatthepatienthasautonomyandisabletoexerciseindividualchoice.Towardsthatend,thephysicianisadvisedtoconsiderthefollowingquestions:

1. Regardingthepatient:

a. Doesthepatienthaveaseriousorimmediatelylife-threateningdiseaseorcondition?

Ifyes,thenask:

b. Hasthepatientexhaustedallcomparableorsatisfactoryalternativeapprovedtherapies?

Ifyes,thenask:

c. Isthepatientacandidateforanyongoingclinicaltrial,consideringtheinclusionandexclusioncriteria,thelocationofthetrial,andotherpracticalandlogisticalchallenges?

Ifthereisanappropriateclinicaltrial,therequestforexpandedaccessislikelytobe

3 McKee,A.E.,Markon,A.O.,Chan-Tack,K.M.,&Lurie,P.(2017).HowOftenAreDrugsMadeAvailableUndertheFoodandDrugAdministration'sExpandedAccessProcess Approved?JournalofClinicalPharmacology,57(S10).


denied.Aspartofthedruganddevicedevelopmentprocess,sponsorsgeneratedatatohelpregulatorsdeterminewhetherornotaninvestigationalproductissafeandeffective.Regulatoryagenciesareobligatedinturntoreviewthesubmitteddataandrenderadecisionregardingsafetyandefficacy.Ifapproved,theproductwillthenbemadegenerallyavailable.Whilethefiduciaryresponsibilityofaphysicianistotheindividualpatient,theresponsibilityofregulatoryagenciesistothehealthofitspopulation,andofthesponsorformakingproductsavailableforsocietalbenefit.Therefore,expandedaccessshouldonlybeconsideredwhentheproductcannotbeprovidedwithinanongoingandenrollingclinicaltrial.

2. Regardingtheinvestigationalproduct:

a. Whatisknownabouttherisks,toxicities,andpotentialbenefitoftheinvestigationalproduct?

i. Itmaybehelpfultoaskthepatientforanyinformationthatheorshemayhave.

ii. Themedicalliteraturemaybehelpful,butmaynotreflectinformationfromon-goingorrecentstudies.

iii. Thesponsormayhaveinformationnotavailableintheliteratureorothermeans.Itisalwaysworthtryingtocontactthecompanytoaccessinformationthattheymayhave(seebelow).

Thesponsormaydeclinetoofferexpandedaccesstotheinvestigationalproductforanumberofreasonsincluding(1)informationthatithasobtainedfromothertrials,(2)lackofsufficientproductavailabilitysuchthatprovisiontotheindividualpatientmayorwillcompromisecompletionofaclinicaltrialorthedrugdevelopmentprogram,or(3)logistical,financialorotherreasons.Thecompanymaynotrelease,andisundernoobligationtorelease,information,particularlyifincomplete.

3. Regardingtreatmentandsubsequentsteps:

a. Ifthepatientisanappropriatecandidateandtherisksofadministrationoftheinvestigationalproductisacceptableinlightofthealternatives,then:

i. Doesthepatientunderstandtherisksofthetreatmentandisheorshewillingtoproceed?

ii. Istheplannedcourseoftreatmentdefined?Generally,the“course”oftreatmentisdeterminedasacomponentoftheapprovalprocesswiththeFDAafterallthedatafromtheproductdevelopmentprogramhasbeenanalyzed.Inexpandedaccessprograms,however,thisinformationisnotyetavailable.Physicianswillfindithelpfultoextrapolatefromthetreatmentplanofanongoingclinicaltrialwithinclusionandexclusion


criteriathatmostnearlymatchthepatientandtodiscusstheplanwiththesponsor.Thatsaid,itisimportanttooutlinetheindividualizedtreatmentplan,aswellastheoutcomemeasuresthatwillbeusedtocontinueordiscontinuetreatment,totheextentpossibleinadvanceofinitiatingtheexpandedaccessprogram.

b. Thephysicianwillhavesignificantresponsibilitiesinhisorherrolenotonlyasthetreatingphysicianbutalsoasthesponsor-investigatorinthiscontext.4Itisimportanttoknowthoseresponsibilitiesandthevariousprocessesandproceduresthatarenecessary,involvingtheinstitutionalreviewboard(IRB)/researchethicscommittee(REC),thesponsoringcompany,andtheregulatoryagency.Thediscussionbelowandthedelineationofthestepsinvolvedaremeanttobehelpfulinthatregard.

2.3RegulatoryBackground

WewillfocusontheprocessesandregulationsintheUSalthoughlocallaws,regulationsandguidance5aswellassponsorrequirementsmustbeconsultedinadvanceofproceedingwithanyrequest.IntheUS,theUSFoodandDrugAdministration(FDA)hasdevelopedprogramsandprocessestoassistpatients,physiciansandtheindustryintheprovisionofinvestigationalproductswhenthereisnocomparableorsatisfactorytherapyavailabletodiagnose,monitorortreatthepatient’sdiseaseorcondition(21C.F.R.§312SubpartI).Asuseofaninvestigationalproductisenvisionedinallprograms,submissionofan“investigationalnewdrug(IND)”or“investigationaldeviceexemption(IDE)”applicationtotheFDAisrequired.Asageneralmatter,thepurposeistoprovideaccesstoproductsforpatientsthatareseriouslyillorhavelife-threateningdiseasesorconditions,nottodevelopgeneralizableknowledgeregardingthesafetyorefficacyofaproduct.

TheFDAhasdevelopedprogramsforwidespreadtreatmentuseofproducts(a“treatmentIND”),intendedforpatientswithseriousorimmediatelylife-threateningdiseasesorconditionsusuallyduringthetimeperiodwhenclinicaltrialshavebeencompletedandthesponsorispursuingregulatoryapproval(21C.F.R.§312.320)andforintermediate-sizepatient 4 Becausethetreatingphysicianwillbefunctioningasasponsor-investigator,andinthiscase,prescribingtheproductunderanindividualpatientIND/IDE,weadvisethephysiciantoensurethatprescribingtheunapprovedproductisa“covered”activityunderthedoctor’sprofessionalliabilitypolicy. 5Otherjurisdictionshavespecificregulations.TheEuropeanMedicinesAgency,forinstance,hasdescribedhowprogramsmaybecreatedintheEuropeanUnion;however,eachEUMemberStateisresponsibleforcoordinatingandimplementingitsownprogram(EMA,2010).IntheUK,theMedicinesandHealthcareproductsRegulatoryAgency(MHRA)isresponsibleforoverseeingthe“earlyaccesstomedicinescheme(EAMS),”athreestepprocess(MHRA,2014).InIndia,pertheDrugsandCosmeticAct1940andRules1945,DrugControllerGeneralofIndia(DCGI)providesoversightofanunapproveddruginthecountrybyapatient(Rule36)orbyahospitalorinstitution(Rule34)(CDSCO,2014.)CodifiedguidanceforexpandedaccessincertaincountriessuchasChinadoesnotappeartobereadilyavailable.Itisalwaysimportanttoconsultlocalregulatoryagenciespriortoproceedingwithexpandedaccess.Theconsiderationsdiscussedhereareapplicabletotheevaluationoftheappropriatenessofexpandedaccesstoinvestigationalproductsforanyindividualpatient.


populationsinsettingsinwhichtheFDAhasreceivedmultipleexpandedaccessrequestsforthesameindication(21C.F.R.§312.315).ThesetwoprogramsdifferfromtheprogramofexpandedaccesstoINDsforanindividualpatientinthattheFDAhasalreadyapprovedtheprogramandaclinicalresearchprotocolhasalreadybeenwritten,reviewedandapprovedbyoneormoreIRBs/RECs.6(seeFigure1).

Figure1.TypesofExpandedAccessThatOccurDuringtheFDA’sDrugDevelopment/ApprovalProcess

From:USGovernmentAccountabilityOffice.FDAhastakenstepstoimprovetheexpandedaccessprogrambutshouldfurtherclarifyhowadverseeventsdataareused.GAO17-564.ReleasedJuly11,2017.https://www.gao.gov/products/GAO-17-564.AccessedNovember25,2017

6 InstitutionalpolicymayrequirethatthephysicianneverthelesshavetheprotocolreviewedbyhisorherlocalIRB/REC,buttheprocessisusuallymuchsimplertoexecute.


TheprogramofexpandedaccesstoINDsforanindividualpatient,includingthatforemergencyuse,isgivenin21C.F.R.§312.310.Onlyexpandedaccessprogramsforaninvestigationalproducttobeusedforthetreatmentofanindividualpatientbyalicensedphysician,willbediscussedhere.

Thetreatingphysicianshouldbeawarethatthereareseveralstepsinobtainingexpandedaccessforanindividualpatient.Theseincludepatientassessmentandevaluation;contactwiththeproductmanufacturerordrugsupplier(the“sponsor”andusuallythepharmaceuticalordevicecompany)7withorwithoutarequestforaletterofauthorization(LOA);submissionofanindividualpatientexpandedaccessINDorIDEsupplementtotheFDA,andFDAreviewandapproval;submissionofaprotocolandinformedconsentdocumentsubmissiontoaninstitutionalreviewboard(IRB),andIRBreviewandapproval;andreportingandfollowupobligations.Werecommendthatthephysiciancontactthesponsorimmediatelyafteradecisionisreachedtorequestexpandedaccessand,ifthesupplieragreestoprovidetheproduct,thatthatbothFDAandIRB/RECapplicationsbesubmittedessentiallyconcurrently.RecentexperiencehasshownthatFDAapproves>99%ofallexpandedaccessrequestsforindividualpatientsitreceivesandinatimelyfashion.8IRBreviewandapprovalmaytakelongerthan,andmayfollow,theprocessattheFDA.Note,however,thattheproductmaynotbegiventothepatientuntilbothFDAandIRBapprovalshavebeenobtained.

Therearetwotypesofindividualpatientexpandedaccessrequests:(1)Non-Emergencyand(2)Emergencyrequests.Forallnon-emergencycases,theFDAandIRBmustreceiveawrittenapplicationinadvance.Whenapatient’sconditionisdireandthereisinsufficienttimetosubmitawrittenapplication,aphysiciancanrequestexpandedaccessfromtheFDAoverthephone(seebelow).Atthattime,theFDAwilldecidewhetherornottheexpandedaccessrequestcanproceedasanemergencyrequest.Nevertheless,therequestingphysicianmustsubmittheapplicationtotheFDAwithin15workingdaysofapproval;theprocessesthereforearenotdifferentinsubstance,onlyintiming.TheIRBmayalsoreviewanapplicationasanemergency;followupwrittendocumentationmustbesubmittedwithinthetimeperiodspecifiedbyinstitutionalpolicyoftheresponsibleIRB(usually5days).9

7Weusethegeneralterm“sponsor”todenotethatentitythathastheabilitytoreviewadapprovetheprovisionoftheinvestigationalproduct,andcansupplytheproductifapproved.Generally,thisisthepharmaceuticalordevicecompanythatmanufacturestheproduct,butmaybeadrugordevicesupplierordesignee.Occasionallyotherentities(e.g.governmentagencies)willbethecognizantagencyabletoreview,approve,andreleasetheproduct.Theterm“sponsor”usedhereshouldnotbeconfusedwiththe“sponsor”oftheindividualpatientexpandedaccessINDapplicationtotheFDA.8 Jarow,J.P.,Lemery,S.,Bugin,K.,Khozin,S.,&Moscicki,R.(2016).Expandedaccessofinvestigationaldrugs:theexperienceoftheCenterofDrugEvaluationandResearchovera10-yearperiod.Therapeuticinnovation&regulatoryscience,50(6),705-709. 9 WerecommendthatthetreatingphysiciancontacthisorherinstitutionalIRBoranindependentorrecommendedIRBassoonaspossibleafterthesponsoragreestomaketheinvestigationalproductavailable.(seeSection2.4below)


ThetreatingphysicianmaysubmitFDAForm392610totheFDAinordertorequestindividualpatientexpandedaccessIND/IDE.ReleasedinJune2016,FormFDA3926isanelectronic,streamlinedapplicationforrequestingindividualpatientexpandedaccess,forwhichdetailedinstructionsforcompletionhavebeenmadeavailable.11IfforsomereasonForm3926cannotbeused,theindividualpatientexpandedaccessINDmaybesubmitted,perFormsFDA157112and1572,13asaprotocolamendmenttoanexistingINDifamenabletothesponsor(usuallythepharmaceuticalcompany).Alternatively,theIND/IDEmaybesubmittedasanewapplicationbythetreatingphysician“underwhoseimmediatedirectionaninvestigationaldrugisadministeredordispensedforanexpandedaccessuse.”14WerecommendthatthetreatingphysicianutilizeFormFDA3926wheneverpossible.

Forexpandedaccesstoadevice,thesponsorwillhavetosubmitanIDEsupplementtotheFDA(21C.F.R.§824.35).IncaseswhereadevicedoesnothaveanIDEfiledwiththeFDA,thephysicianandsponsorwillneedtocontacttheFDA(SeeSteps2and3,below).

ThetreatingphysicianservesastheINDsponsor-investigator(21C.F.R.§312.305(c)(3))andshouldbefamiliarwithhisorherrolesandresponsibilities,includingsecuringinformedconsentfromthepatientafterreviewandapprovalbyaninstitutionalreviewboard(IRB);maintainingandreporting,asrequired,casereports,drugdispositionandadverseeventrecords;andotherresponsibilities.Often,thenewINDwillreferenceanexistingINDwithpermissionofthesponsor.Thechecklistandtoolsprovidedherearemeanttoassistthetreatingphysicianinpursuingexpandedaccessforthepatient.

Severalresourcesforrequestingexpandedaccesscurrentlyexistforpatients,patientadvocates,andphysicians,including:

• KidsvCancer(https://www.kidsvcancer.org/)hascreatedaCompassionateUseNavigator15thataimstoassistthepediatriconcologycommunityinunderstandingandapplyingforexpandedaccess.Inaddition,KidsvCanceralsoprovidespersonalizedassistancetopatientspursuingexpandedaccessandtophysicianssubmittingrequestsandreportstothesponsor,FDA,andIRB.

10 https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504572.pdf 11 InstructionsforfillingoutformFDA3926–IndividualPatientExpandedAccess,InvestigationalNewDrugApplication(IND).Availableat:https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504574.pdf.AccessedNovember25,2017. 12HHSFDAInvestigationalNewDrugApplication.https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083533.pdf,andinstructionaldirectionsforcompletion:https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM182850.pdfAccessedNovember25,2017.13HHSFDAInvestigationalStatementofInvestigator.https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf14https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.30515SeeKidsvCancer,“CompassionateUseNavigator.”http://www.kidsvcancer.org/compassionate-use/.AccessedNovember25,2017.


• TheRegan-UdallFoundation(http://reaganudall.org/)fortheFoodandDrugAdministrationhasdraftedplansforanExpandedAccessNavigator,16whichwillaimtobeaneducationalresourceforpatientsandhealthcareprovidersaswellasacentralizedresourceforinformationaboutrequestingindividualpatientexpandedaccess.

• TheRegulatoryAffairsProfessionalSociety(RAPS;http://www.raps.org)hascreatedaguide17totheFDA’sregulationsonexpandedaccess.

• HarvardCatalyst,theHarvardClinicalandTranslationalScienceCenter,hascreatedaPhysicianChecklisttoObtainExpandedAccessINDforTreatmentoftheIndividualPatient.18

2.4Physician’sToolkitStep1. PatientAssessment

q PatientEvaluation:Whenconsideringexpandedaccesstoaninvestigationalproduct,aphysicianmustevaluatetherisksofprovidingtheinvestigationalproductagainsttherisksofthepatient’sdiseaseorcondition.Thepatientmusthaveaseriousdiseaseorcondition,forwhichnoalternativecomparabletreatmentexists.Additionally,anyextantclinicaltrialsshouldbeclosedorinaccessibletothepatient(seehttps://clinicaltrials.gov).

q Determinepatienteligibility(21C.F.R.§312.300)andwhetheremergencyornon-emergencyindication(Box1):

Box1:Non-EmergencyUseandEmergencyUseq Thepatienthasan“seriousdiseaseorcondition.”(SeeAppendixI:Glossary

andDefinitions)

q Therearenoalternativecomparableorsatisfactorytreatmentsthatareapprovedandavailabletothepatient.

q Therearenoclinicaltrialsopenoraccessibletothepatient.19

q Thepotentialbenefitsofprovidingtheinvestigationalproducttothepatientoutweighthepotentialrisks.

16SeeReagan–UdallFoundationfortheFoodandDrugAdministration,“DraftProjectProposal:ExpandedAccessNavigatorforIndividualPatientAccess.”http://navigator.reaganudall.org/about.AccessedNovember25,2017.17SeeRegulatoryAffairsProfessionalSociety(RAPS),“RegulatoryExplainer:FDA'sExpandedAccess(CompassionateUse)Program.”http://www.raps.org/Regulatory-Focus/News/2015/02/04/18343/Regulatory-Explainer-FDAs-Expanded-Access-Compassionate-Use-Program/.AccessedJanuary10,2017.18 HarvardCatalyst.HarvardClinicalandTranslationalScienceCenter.PhysicianChecklistToObtainExpandedAccessINDForTreatmentOfIndividualPatient.https://catalyst.harvard.edu/pdf/regulatory/Single_Patient_IND.pdf.AccessedNovember25,2017. 19PleaseseeClinicalTrials.gov,anonlinedatabaseofclinicaltrialsworldwide,todeterminewhetherornotanyclinicaltrialsareopentothepatient.https://clinicaltrials.gov.AccessedJanuary10,2017.


EmergencyUseOnly

q Isthepatient’sdiseaseorcondition“immediatelylife-threatening”?(SeeAppendixI:GlossaryandDefinitions)

q IsthereinsufficienttimeforFDAsubmissionandIRBreview?

Ifthepatientmeetsthecriteriaabove,thephysicianmustthenrequestthesponsortoprovidetheproduct,providingsufficientinformationforthesponsortomakeanappropriatedecision.InordertorequestaLetterofAuthorization(Step2)fromaSponsorandinordertocompleteFDAForm3926(Step3),thefollowinginformationaboutthepatientandproductisneededandshouldbecollected(Box2):

Box2:NecessaryPatientandProductInformationPatientInformation:q Ageq Genderq Weightq Allergiesq Diagnosisq Clinicalhistoryq Priortherapiesandresponses:q Explanationofwhypatient’slack

othertherapeuticoptionsq Rationaleforrequestingexpanded

access

ProductInformationq ProductNameq Manufacturerq Indicationq TreatmentPlan(Dosage;Meansof

Administration;Duration;MonitoringProcedures)

Step2. ApprovalfromSupplier/Manufacturer(the“sponsor,”usuallythepharmaceuticalor

devicecompany)

Thephysicianmustcontactthesupplier/manufacturer(“sponsor”)toensurethatthesponsorwillagreetoprovidetheinvestigationalproduct,ifapprovedbytheFDAandIRB.Itisoftenadvisabletocontactthesponsorearlyintheprocessofconsideringexpandedaccessforthepatient:thesponsorwillgenerallyhaveinformationabouttheinvestigationalproductthatisdifficulttoaccessbyanyothermeans.Thesponsorwillalsobeabletoinformthephysicianofongoingclinicaltrialsthatmaybeappropriateforthepatient,ofintermediate-sizeortreatmentINDavailability,orofpriorexperiencewithexpandedaccess(andpotentialIRBandFDAcontacts).Pleasenotethatasponsormaynot,andisundernoobligationto,approvetherequestevenifthepatientmeetseligibilityforexpandedaccess.

Inbothemergencycasesandnon-emergencycases,thesuppliermustagreetoprovidetheinvestigationalproduct.


q Thephysiciancontactsthesponsor:Thephysicianmustcontactthesponsortoensurethatthesponsorwillprovidetheinvestigationalproduct.The21stCenturyCuresAct,passedinDecember2016,requiressponsorstomaketheirpoliciesforprocessing,evaluating,andrespondingtoexpandedaccess(alsotermed‘compassionateuse’)publiclyavailable.Thepolicywilldetailthetermsofaccess,criteriaforreviewandapproval,andprocessesbywhichtreatingphysicianscanrequestaccessifappropriate.

Therequestingphysicianmayberequired,forexample,tosubmitaformonlineortocontactasponsorrepresentativedirectly.Pleasenotethatpolicies,processes,andpointsofcontactwillvaryfromsponsortosponsor.

q Thesponsoragreestoprovideexpandedaccess.Forfactorsconsideredbysponsorswhendecidingwhetherornottoprovideexpandedaccess,seetheMRCTCenter’sResourcesforSponsorsProvidingExpandedAccesstoInvestigationalProducts(Section1).

q Fordrugsandbiologics,thephysicianrequestsaLetterofAgreement(LOA)fromthesponsor:TheLOA(whichwillbeincludedintheFDAsubmissionforapproval)shouldlistthesponsor’sINDnumber.IntheeventthattheproductdoesnothaveanINDapplicationalreadysubmittedtotheFDA,thephysicianshouldcontacttheFDAforguidanceonwhatinformationtoprovideaboutdrugsupplyandsafety.

q Fordevices,thephysicianrequeststhesponsortosubmitanIDESupplement:Inthecaseofinvestigationaldevices,thesponsorwillusuallyhaveaninvestigationaldeviceexemption(IDE)filedwiththeFDA(21C.F.R.§812).ThesponsorwillthensubmitanIDESupplementtotheFDA(21C.F.R.§812.35).IncaseswherethesponsordoesnothaveanIDEapplicationattheFDA,thephysicianandsponsorwillneedtocontacttheFDAdirectly.(SeeStep3).

Step3. FDASubmission:

Tosubmitanon-emergencyrequestforindividualpatientexpandedaccesstoaninvestigationaldrug,thephysicianmustsubmiteither• Form3926(preferred)

Link:http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504572.pdfPleasenoteForm3926mustbeopenedinInternetExplorer,anditmaybenecessarytodownloadinordertobeopenedandcompleted.Attendtotheboxed“Importantinformation”atthetopofthepage.Instructions:http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM504574.pdf


Guidance:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM432717.pdf

ForsubmissionofForm3926,thefollowinginformationisnecessary(andseeBox2and3):

• Aconciseclinicalhistoryofthepatient• Theentity(usuallythemanufacturer)thatwillsupplytheinvestigationalproduct

andthenameoftheproduct• Thetreatmentplan,includingdose,routeandscheduleofadministration,duration

oftherapy,plannedmonitoringprocedures,andplannedmodificationstotherapyintheeventoftoxicity

• Letterofauthorization(LOA)fromtheentityprovidingtheproduct• Informationconcerningyoureducation,training,specialty,licensure(including

number),experience,currentemploymentandjobtitle.Acurriculumvitae(CV)maybesuppliedinstead,ifitcontainstherequiredinformation

• Signaturetoindicateyouwillfulfillallapplicableregulatoryrequirements,including:o Thatyouwillnotbegintreatmentuntil30daysafterreceiptofthe

applicationbytheFDA,unlessnotifiedbytheFDAotherwiseo Thatyouwillnotbeginorceasetreatmentiftheinvestigationproductisput

onclinicalholdo ThatyouwillnotbegintreatmentpriortoIRBreviewandapprovedofthe

treatmentuse,andthattheIRBwillberesponsibleforinitialandcontinuingreview

o Thatyouwillobtaininformedconsentfromthepatiento That,intheeventofemergencyuse,youwillabidebytheemergencyuse

requirements• Forms1571and1572

Link(1571):http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083533.pdfInstructions:http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM182850.pdfLink(1572):http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdfInstructions:http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM223432.pdf


Form3926isashorter,streamlineddocumentdesignedspecificallyforsinglepatientrequests,andwerecommendtreatingphysiciansuseForm3926.IfforsomereasonForm3926cannotbeused,Forms1571and1572mayalsobesubmittedforsinglepatientINDrequest.WhenmedicalnecessitydictatesthatthereisinsufficienttimetoprepareandsubmitForm3926(orForms1571and1572),thephysicianmaysubmitanemergencyrequestforindividualpatientexpandedaccesstoaninvestigationaldrugbycontactingtheFDAdirectly(seechart,below).Iftherequestisapproved,thephysicianisexpectedtosubmitForm3926(orForms1571and1572)within15workingdaysoftheinitialapproval.Formoreinformationaboutexpandedaccesstoinvestigationaldrugsfortreatmentuse,pleasesee:http://www.fda.gov/downloads/drugs/guidances/ucm351261.pdfTosubmitanon-emergencyrequestforindividualpatientexpandedaccesstoaninvestigationaldevice,thesponsor(usuallythedevicemanufacturer)mustsubmittotheFDAanIDEsupplementalrequestforexpandedaccess(21C.F.R.§812.35(a)).20Inthecaseofanemergencyrequestforindividualpatientexpandedaccesstoaninvestigationaldevice,theunapproveddevicemaybeusedwithoutpriorapprovalbytheFDA.Eveninthesecases,however,thetreatingphysicianisexpectedtofollowappropriatemeasurestorespectthepatient’sautonomy,includinginformedconsent,theconcurrenceoftheIRBchairpersonordesignee(seeSectionXX,ResourcesforIRB),assessmentbyanuninvolvedphysician,sponsorauthorizationtoprovidethedevice,andanylocalinstitutionalapprovalsthatarerequired.Theinstitutionalprocessforemergencyapprovalofinvestigationalproductsisusuallyoutlinedininstitutionalpolicies;thetreatingphysicianshouldcontacttheappropriateinstitutionalresource.Thesponsormuststillreporttheemergencyusewithin5daystotheFDA,fillingouttheIDESupplement(21C.F.R.§812.35(a(2)).IfnoIDEexists,thetreatingphysicianmustsubmitareportonemergencyuseofthedeviceto:

FoodandDrugAdministrationCenterforDevicesandRadiologicalHealth10903NewHampshireAveDocumentControlCenterWO66RmG-609SilverSpring,MD20993

ForacompletelistofcontactinformationforsubmittingarequestforexpandedaccesstotheFDA,pleasesee:http://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/ucm429610.htm

20Forguidanceonrequestingexpandedaccesstodevices,pleaseseeFDA,“ExpandedAccessforMedicalDevices.”https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm.AccessedNovember23,2017.


Box3:ChecklistforEmergencyandNon-EmergencyExpandedAccessProcedures

Non-EmergencyCases

q FDAForm3926,IndividualPatientExpandedAccessApplicationTocomplete,youwillneedthefollowing:q Indicationq Patienthistoryandinformation(patient

initials,indicationandproposedtreatmentuse,briefclinicalhistoryincludingage,gender,weight,allergies,diagnosis,priortherapiesandresponses,reasonforrequest,explanationoflackofothertreatmentoptions)

q Investigationaldrugnameq Manufacturer/suppliernameq ApplicableFDAreviewdivision,see

http://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/ucm429610.htm

q Treatmentplan(planneddose,routeandscheduleofadministration,planneddurationoftreatment,monitoringprocedures,andanyplannedmodificationsintheeventoftoxicity)

q Physician'squalificationstatement/physician’sCV

q Physiciancontactinformationq LetterofAuthorization(LOA,referencing

thesponsor’sINDnumber).q Checkbox10AonForm3926,indicatinga

requestforauthorizationtouseForm3926.q Checkbox10BonForm3926,indicatinga

requestforauthorizationtousealternativeIRBreviewprocedures.

Or:

EmergencyCases

q Duringbusinesshours(8AM–4:30PMESTweekdays),thetreatingphysicianshouldcontactthefollowingdepartmentsattheFDA:

q InvestigationalDrugsCDER’sDivisionofDrugInformation(DDI)Phone:855-543-3784or301-796-3400ortheappropriateCDERReviewDivision(seeAppendixB.)

q InvestigationalBiologicsCBER'sOfficeofCommunication,Outreach,andDevelopmentPhone:240-402-7800or800-835-4709Email:[email protected]

q InvestigationalDevicesCenterforDevicesandRadiologicalHealth(CDRH)Phone:301-796-5640Fax:301-847-8120

q Outsideofbusinesshours

(weekends;after4PM(EST)onweekdays),thetreatingphysicianrequestingexpandedaccessforemergencyuseofdrugs,biologics,anddevicesshouldcontactTheFDAEmergencyCallCenterPhone:866-300-4374

Electronicandfacsimilecommunicationsarenotmonitoredduringthistime.

q FDAForm1571:InvestigationalNewDrugApplication.WedonotrecommendForm1571and1572inplaceofForm3926.Thephysicianshouldselect“IndividualPatient,


Non-Emergency”or“IndividualPatient,Emergency”inSection12.Additionally,thephysicianmustprovide:q Singlepatientrequeststatementq Patienthistoryq Treatmentplanq Productinformationq Informedconsent

q FDAForm1572:StatementofInvestigator:

ThismustaccompanyForm1571.

q Thedecisiontoauthorizeordenyemergencyexpandedaccesswillbecommunicatedbytelephone.

Noteadditionalrequirements:

q AllnecessaryformsandinformationmustbesubmittedtotheFDAwithin15workingdaysofFDAauthorizingaccess

q EmergencyusemustbereportedtotheIRBwithin5workingdaysoftreatmentinitiation

PleasealsoseeupdatedFDACDERprocessesandproceduresathttps://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM572098.pdf.

Tosubmitforexpandedaccesstoaninvestigationaldrug,physiciansshould

q CallCDERDivisionofDrugInformation(DDI)at855-543-3784or

q [email protected] Mailrequestto

FoodandDrugAdministrationCenterforDrugEvaluationandResearchCentralDocumentRoom5901-BAmmendaleRd.Beltsville,Md.20705-1266

Tosubmitforexpandedaccesstoaninvestigationalbiologic,physiciansshouldeither

q CallCBER240-402-8010or800-835-4709;or

q [email protected] Mailrequestto:

FoodandDrugAdministrationCenterforBiologicsEvaluationandResearchDocumentControlCenter10903NewHampshireAvenueWO71,G112SilverSpring,MD20993-0002


q IDESupplementalrequestforexpandedaccess(21C.F.R.§812.35(a)).21

q Patientconditionq Rationaleforrequestingexpandedaccess

(lackofalternativeapprovedtreatments;benefit-riskanalysisofusingtheinvestigationaldevice.)

q DeviationsfromtheclinicaltrialprotocolasdescribedintheIDE.

q Informedconsentdocumentq Institutionalclearanceq IRBchairpersonapproval(PleaseseeStep4,

below).q Independentassessmentofanuninvolved

physicianq Authorizationofdevicemanufacturer

IninstanceswherethesponsordoesnothaveanIDEwiththeFDA,thesponsormustalsoinclude:

q DescriptionofdeviceTosubmit,physiciansshould

q CalltheCenterforDevicesandRadiologicalHealth(CDRH)at301-796-5640.

q FaxtherequesttoCDRHat301-847-8120q Emailrequestto

[email protected] Mailrequestto:

FoodandDrugAdministrationCenterforDevicesandRadiologicalHealth10903NewHampshireAveDocumentControlCenterWO66RmG-609SilverSpring,MD20993

21Forguidanceonrequestingexpandedaccesstodevices,pleaseseeFDA,“ExpandedAccessforMedicalDevices.”http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm051345.htm.AccessedJanuary5,2016.


q FDAResponse

Approval:IftheFDAapprovesanemergencyINDrequest,treatmentwiththedrugcanbeginoncethephysicianhasobtainedinformedconsentfromthepatientorlegallyauthorizedrepresentative.Note:thephysicianshouldcontacttheIRB,however,toensureconformancewithinstitutionalpoliciesandfollow-upwiththeIRBappropriatelythereafter.Innon-emergencycasesofexpandedaccessrequeststoINDsorIDEs,theFDAwillnotifytherequestingtreatingphysician(sponsor-investigator)inatimelymanner,oftenwithindaysofsubmission.However,thephysicianmaybegintreatingthepatientwiththeinvestigationalproduct30daysaftertheFDAreceivestherequestifthereisnoresponsefromtheFDA.ThetreatingphysicianshouldfeelfreetocontacttheFDAdirectlyifnoresponseisreceivedandfurtherdelaywouldbedetrimentaltothepatient.Iftheapplicationisapproved,anINDnumberwillbeassigned.ThatINDnumbershouldbesuppliedtothemanufacturer(sponsor)sothattheinvestigationalproductcanbeshipped.TreatmentmaybeginafterFDAreviewandapproval(ortheFDAhasnotresponded30daysfollowingsubmission),IRBreviewandapprovaloftheprotocol,andthepatienthasgiventheirvoluntaryinformedconsent.Disapproval:Iftreatmentuseisnotapproved,FDAwillgenerallynotifythephysicianbytelephone,followedbywrittencommunication.

Step4. IRBSubmission,reviewandapproval:

WhenthephysiciansubmitsarequesttotheFDA,thephysicianagreesthatanIRBwillreview,approve,andoverseetheprovisionoftheinvestigationaldrug,biologic,ordevice.Recently,andinresponsetothe21stCenturyCuresAct,theFDAmodifieditsexpectationthataconvenedIRBwillreviewexpandedaccessrequestsfordrugsandbiologicsandanIRBchairpersonwillreviewrequestsfordevices.AsofOctober2017,anIRBchairpersonorotherappropriatedesigneecannowapprovethetreatmentrequest.WerecommendthataphysiciancontactthereviewingIRBassoonasadecisiontopursueexpandedaccessismade.EachIRBshouldhavewrittenproceduresregardingtheirprocessesforreviewingexpandedaccessrequests,and,asaresult,IRBrequirementsmaydiffer.

DrugsandBiologics(INDs)Innon-emergencycases,atreatingphysicianrequestingexpandedaccesstoaninvestigationaldrugorbiologicshouldsubmitthefollowingtotheIRB:

q Explanatoryletterwithrationaleforrequestingexpandedaccessincludingsufficientclinicalandmedicalinformationthatareasonablepersonisabletoformanindependentopinion,proposedtreatmentplan,outcomemeasuresthatwillbeusedforevaluation,andmonitoringplan

q Informedconsentdocumentq FDAForm3926q InvestigatorsBrochure


q SponsorLOAq AnyadditionalmaterialsthatthereviewingIRBrequiresaccordingtoitswritten

procedures

Inemergencycases,wheretheFDAhaddeterminedtheprovisionofthedrugorbiologiccanoccurimmediately,thephysicianisrequiredtoreporttosubmitthesamedocumentationtotheIRBwithin5workingdaysofbeginningtreatmentwiththeinvestigationalproduct(21C.F.R.§56.104(c)).22Nevertheless,aphysicianshouldengagewiththeIRBasearlyaspossible,astheresponsibleIRBcanassistaphysicianwithnavigatingitsspecificproceduresandreviewprocess.

Devices(IDEs)Innon-emergencycases,thetreatingphysicianmustseektheconcurrenceoftheIRBchairpersonconcurrentlywiththeapplicationtoFDA.IftheIRBchairpersonwillnotapprovetheuseofthedevicepriortoFDAapproval,thetreatingphysicianshouldindicatethatIRBapprovalwillbeobtainedpriortoadministeringthedevice.Thisapprovalmustthenbesubmittedinafollow-upreporttotheFDA.Inemergencycases,andsimilartotheexpectationsfordrugsandbiologics,thetreatingphysicianisexpectedtorespectthepatient’sautonomy,includinginformedconsent,theconcurrenceoftheIRBchairperson,assessmentbyanuninvolvedphysician,sponsorauthorizationtoprovidethedevice,andanyadditionallocalinstitutionalprocessesandapprovals.ThetreatingphysicianmustreporttheuseofanIDEtotheIRBwithin5workingdays.ForphysicianswithoutaccesstoanIRB,submissionscanbefiledwithanindependentIRB.TofindalocalIRB,theOHRPDatabaseofRegisteredIRBsmaybehelpful.TheIRBwilldeterminewhetherthetreatmentplan,plannedapproach,informedconsentdocument,andproposedfollowupplanisapproved.OnlywithIRBapprovalmaytheinvestigationalproductbeadministered.

Step5.ObtainInformedConsentfromthePatientorLegallyAuthorizedRepresentative.TheinformedconsentshouldfulfilltherequirementsestablishedbytheFDA(21C.F.R.§50SubpartB).Pleasesee:https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50&showFR=1&subpartNode=21:1.0.1.1.20.2.

22Ofcourse,IRBs/RECsmayhaveinstitutionalpoliciesthatrequiresubmissionofwrittenmaterialssoonerthan5workingdays.ThewrittenproceduresandpoliciesofthereviewingIRBshouldbefollowedifmorerestrictive.


Step6.PhysicianResponsibilities:Whenaphysiciansubmitsarequestforexpandedaccesstoaninvestigationalproductonbehalfofapatient,thephysicianisconsideredthesponsor-investigator.Assuch,thephysicianisresponsibleforensuringthattheprovisionofexpandedaccessisexecutedasproposedintheForm3926(orForm1571andForm1572),andforrecordingandreporting:

q Productaccess:

Thephysicianmustarrangewiththesponsortoreceivetheinvestigationalproduct.o Createplan,withsponsor,forobtainingtheinvestigationalproduct

o Maintainproductdispositionrecords,includingreturnordestructionofunusedproductandissuanceofacertificateofdestructionifrequired

q Maintenanceofadequaterecordsof(1)casehistoryandobservationsrelatedtoprovisionofproduct,includingadverseevents;and(2)dispositionofinvestigationalproduct,includingdates,quantityanduse.See:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm362663.htm

q Safetyreportsforadverseevents

o TotheFDA(seehttp://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm362555.htm)

§ Seriousandunexpectedadversereactionsmustbereportedasasuspectedadversereactiononlyifthereisevidencethatthereisacausalrelationshipbetweentheinvestigationalproductandtheadverseevent(21CFR312.32(c)).

o TotheIRB

§ WrittenIRBproceduresshouldbefollowed

q Treatmentplanamendments


o TotheIRB

§ WrittenIRBproceduresshouldbefollowed

q INDAnnualreportsifthetreatmentuseextendsbeyondoneyear



q IRBcontinuingreviewreportifthetreatmentuseextendsbeyondoneyear

o Applicationforcontinuedreview,perwrittenIRBprocedures

q ForIDE,asemi-annualprogressreport:

o TotheFDAandIRB(see:http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046717.htm

q SummaryreporttosponsorandFDA

o Sincethetreatingphysicianisfunctioningasthesponsor-investigator,heorsheassumestheresponsibilitytoprovideFDAawrittensummaryoftheresultsoftheexpandedaccessuse,includingadverseeffects,asdetailedintheregulations(§312.310(c)(2)).


3. ResourcesforIRBs/RECs:EvaluationofRequestsforInvestigationalProductsThroughtheIndividualPatientExpandedAccessProgram

3.1BackgroundInadditiontophysiciandeterminationofneedandappropriateness,manufacturerorcompanyreviewandapprovalofarequestfortheinvestigationalmedicine,andFDAreviewandapprovalofasingle-patientINDoraprotocolamendmenttoanexistingIND,expandedaccesstoadrugforanindividualpatientrequiresIRB/RECreviewandapprovalofanapplicationforuse.IntheUS,thelatterrequirementisaconsequenceofFDAregulationsregardingoversightoftheadministrationofthe(IND-authorized)investigationalproduct.IRBreviewisintendedtoassurethattherightsandwelfareofthepotentialparticipantareprotected,includingthatinformedconsentisvoluntary,informed,andobtainedinadvanceoftreatment.Inthissituation,thepurposeofIRBreviewistoensurethatthepatientunderstandsthattreatmentwillconsistofaninvestigationalproductaboutwhichsafetyandefficacyhavenotbeenestablished.Thepurposeisnotfortheadvancementofgeneralizableknowledge.Overthelastseveralyears,theFDAhasmadesignificanteffortstoreducethebarrierstoexpandedaccessincludingtherequirementsforIRBreviewandapproval.InOctober2017,theFDAamendeditsguidancetoallowaphysiciansubmittinganindividualpatientexpandedaccessINDapplicationtoelecttorequestawaiver,under21CFR§56.105,forreviewbyaconvenedIRBatwhichthemajorityofmemberswerepresent.Insteadofrequiring“full”boardreview,theIRBchairpersonoradesignatedIRBmembermayreviewandapprovetheapplication.23IfthephysicianusesFDAForm3926,Box10bshouldbechecked;ifthephysiciansubmitsFDAForm1571,aseparatewaiverrequestmustbesubmitted.ThewaiverwillbegrantedifthephysicianatteststhatheorshewillobtainapprovalbytheIRBchairpersonordesignatedIRBmember,andinformedconsentbythepatient,inadvanceoftreatment.24BecauseapplicationsforanindividualpatientexpandedaccessINDarerelativelyrareforanIRB,itisworthconsideringthelimitedaspectsofreviewthatarenecessary.HereweexaminethescopeofresponsibilitiesoftheIRBinexpandedaccessprogramsandsuggestmeasuresforsimplificationandprocessimprovement.TheFDAregulations(21CFRpart56)mustbefollowed.PhysiciansarepermittedbybothFDAandtheOfficeofHumanResearchProtections

23ThewaiverprovisiononlyappliestoIRBofanindividualpatientexpandedaccessapplication,notanintermediate-sizeexpandedaccessprogramortreatmentIND.24ExpandedAccesstoInvestigationalDrugsforTreatmentUse.QuestionsandAnswers.GuidanceforIndustry.Question6.https://www.fda.gov/downloads/drugs/guidances/ucm351261.pdf.AccessedNovember23,2017.


regulationstoaccesstheirowninstitutionalIRB,anindependentIRB,oracentralorsingleIRBtooverseehumansubjectsresearch.Thephysicianshouldbeawareoftheirinstitution’spoliciesinthisregard.

3.2ConsiderationsforIRBsinDecision-MakingaboutExpandedAccessAsmentioned,thepurposeofIRBreviewisnottheascertainmentofgeneralizableknowledge,butrathertheassurancethattheindividualpatientisawareofthepotentialrisksanduncertainbenefitsoftheplannedtreatmentusinganinvestigationalproduct.TheIRBshouldconsider:

q Thatthepurposeoftheactivityisclinicalcare,notresearch.q Thatasinglepatientwillbetreated,andthereforenoinclusion/exclusioncriteria,nor

statisticalanalysis,areanticipated.q Thattheclinicalcourseofthepatientisdescribedinadequatedetailtojustifyuseofthe

individualpatientexpandedaccessapplication.SubmissionofthematerialspresentedtotheFDAareoftenadequate.

q Thatthetreatmentplanmakesprovisionstoensurethesafetyofthepatient,includingexpectationsformonitoringandplannedmodificationsofthetreatmentplanintheeventoftoxicityorunanticipatedproblemsthatarethoughttobecausallyrelatedtotheinvestigationalproduct.

q Thattheinformedconsentdocumentandprocessexplaintheuncertaintyoftheproposedtreatmentplan,uncertainbenefitsandpotentialrisksincludingseriousharms,allresearch-relatedprocedures,andthevoluntarynatureofconsent.

q Thatspecialprotectionsareinplacetoensureadequateunderstandingoftheinformedconsent,acknowledgingthatthepatientisvulnerable,

q ThattheprivacyinterestsofthepatientwillbeprotectedtotheextentpossibleandthattherequirementsofHIPAAwillbefollowed.

q Thattherightsandwelfareofthepatientareprotected.q Thatthephysicianunderstandshisorherresponsibilitiesinobtaininginformedconsent,

monitoringandreportingtoallofficesandagenciesandtotheentitythatprovidedtheinvestigationalproduct.Anyspecialreportingrequirementsshouldbeoutlined.

FollowingIRBreview(orexpeditedreviewbytheIRBchairpersonorhisorherdesignee),theIRBwilldeterminewhethertheapplicationisapproved,modificationsrequired,deferred,ordisapproved.Note,researchcannotbedisapprovedbyexpeditedreview,andshouldbereferredtoaconvenedIRB.


3.3GlossaryandDefinitionsImmediatelylife-threateningdiseaseorconditionmeansastageofdiseaseinwhichthereisreasonablelikelihoodthatdeathwilloccurwithinamatterofmonthsorinwhichprematuredeathislikelywithoutearlytreatment.(21C.F.R.§312.300)Investigationaldevice:isadevice,includingatransitionaldevice,thatistheobjectofaninvestigation.(21C.F.R.§812.3)Investigationalnewdrug:meansanewdrugorbiologicaldrugthatisusedinaclinicalinvestigation.(21C.F.R.§312.3)Seriousdiseaseorconditionmeansadiseaseorconditionassociatedwithmorbiditythathassubstantialimpactonday-to-dayfunctioning.Short-livedandself-limitingmorbiditywillusuallynotbesufficient,butthemorbidityneednotbeirreversible,provideditispersistentorrecurrent.Whetheradiseaseorconditionisseriousisamatterofclinicaljudgment,basedonitsimpactonsuchfactorsassurvival,day-to-dayfunctioning,orthelikelihoodthatthedisease,ifleftuntreated,willprogressfromalesssevereconditiontoamoreseriousone.(21C.F.R.§312.300)


4. ResourcesandReferences21C.F.R§312:InvestigationalNewDrugApplication

https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=3b47469566c47db3234b52059e48d203&mc=true&n=pt21.5.312&r=PART&ty=HTMLAccessedNovember27,201721C.F.R.§312SubpartI:ExpandedAccesstoInvestigationalDrugsforTreatmentUsehttps://www.ecfr.gov/cgi-bin/text-idx?SID=c859616b5a665bbcda13092d0c1c063d&node=sp21.5.312.i&rgn=div6AccessedNovember27,2017

21C.F.R.§812:InvestigationalDeviceExemptionshttps://www.ecfr.gov/cgi-bin/text-idx?SID=404baf05c26922d7542aec17055068ef&mc=true&node=pt21.8.812&rgn=div5AccessedNovember27,2017Ainge,D.etal.(2015).GlobalAccessPrograms:ACollaborativeApproachforEffectiveImplementationandManagement.PharmaceutMed,29(2),79–85.http://doi.org/10.1007/s40290-015-0091-9AccessedJanuary10,2017CentralDrugsStandardControlOrganization(CDSCO)(2014),ProcedureforpermissiontoImportSmallQuantitiesofDrugsforPersonalUse.http://cdsco.nic.in/forms/list.aspx?lid=1852&Id=30AccessedJanuary10,2017.EuropeanCommission(EC)(2001),Directive2001/83/ECoftheEuropeanParliamentandoftheCouncil.OntheCommunitycoderelatingtomedicinalproductsforhumanuse.http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_83_cons2009/2001_83_cons2009_en.pdfAccessedJanuary10,2017.–––(2004),RegulationNo.726/2004oftheEuropeanParliamentandoftheCouncil.http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2004R0726:20090706:EN:PDFAccessedJanuary10,2017.EuropeanMedicinesAssociation(EMA)(2007).CommitteeforMedicinalProductsforHumanUse(CHMP).Guidelineoncompassionateuseofmedicinalproducts,pursuanttoarticle83ofregulation(EC)No726/2004.2007.http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004075.pdfAccessedJanuary10,2017.EuropeanMedicinesAssociation(EMA)(2010).“QuestionsandanswersonthecompassionateuseofmedicinesintheEuropeanUnion.”


http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500069898.pdfAccessedJanuary10,2017.FoodandDrugAdministration(FDA)(2009),ExpandedAccesstoInvestigationalDrugsforTreatmentUse,21C.F.R.Sect.312SubpartI.http://www.ecfr.gov/cgi-bin/text-idx?SID=c859616b5a665bbcda13092d0c1c063d&node=sp21.5.312.i&rgn=div6AccessedJanuary10,2017.FoodandDrugAdministration(FDA)(2017)ExpandedAccesstoInvestigationalDrugsforTreatmentUse—QuestionsandAnswers.GuidanceforIndustryhttps://www.fda.gov/downloads/drugs/guidances/ucm351261.pdfAccessedNovember25,2017FoodandDrugAdministration(FDA)(2017)IndividualPatientExpandedAccessApplications:FormFDA3926GuidanceforIndustryhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM432717.pdfAccessedNovember25,2017MedicinesandHealthcareProductsRegulatoryAgency(MHRA)(2014),EarlyAccesstoMedicinesScheme(EAMS).https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eamsAccessedJanuary10,2017.Patil,S.(2016).Earlyaccessprograms:Benefits,challenges,andkeyconsiderationsforsuccessfulimplementation.PerspectivesinClinicalResearch,7(1),4–8.http://doi.org/10.4103/2229-3485.173779AccessedJanuary10,2017.Rahbari,M.andRahbariN.N.(2011).CompassionateuseofmedicinalproductsinEurope:currentstatusandperspectives.BullWorldHealthOrgan,89(3),163.http://doi.org/10.2471/BLT.10.085712AccessedJanuary10,2017.Section801oftheFoodandDrugAdministrationAmendmentsAct(FDAA801)https://clinicaltrials.gov/ct2/manage-recs/fdaaa#DevelopmentOfRegulationsAccessedMarch25,2017.Sou,H.(2010).EUcompassionateuseprogrammes(CUPs):regulatoryframeworkandpointstoconsiderbeforeCUPimplementation.PharmMed,24(4),223–229.http://doi.org/10.1007/BF03256820AccessedJanuary10,2017.UnitedStates.Cong.HouseofRepresentatives.21stCenturyCuresAct.114thCong.H.Res6(2016).https://www.congress.gov/bill/114th-congress/house-bill/6/textAccessedJanuary27,2017.

Documents

MRCT Center Expanded Access to and Institutional Review · 12/1/2017 · survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from